The Impact of HIV-1 Infection on Vitamin a Metabolism and Intestinal Dendritic Cells

Abstract

The intestinal tract is a major site of human immunodeficiency virus type 1 (HIV-1) replication and is thought to play a significant role in disease progression. Studies of the HIV-1 reservoir suggest that the intestinal immune compartment harbors the majority of latently infected cells in the body, constituting a considerable obstacle to viral eradication and cure. Additionally, persistent HIV-1-associated deficiencies in gut immunity and epithelial barrier function are linked to systemic inflammation, which remains heightened even after initiation of antiretroviral therapy (ART). Vitamin A is a known mediator of both intestinal immune homeostasis and effector immunity, working primarily through its active metabolite, all-trans-retinoic acid (atRA). The considerable overlap between atRA-associated processes and the immunological defects seen in progressive HIV-1 infection forms the basis of this study, with a primary aim to determine whether disruption of vitamin A metabolism in gut mucosae contributes to HIV-1 disease progression and persistence. The first aim of this investigation focuses on intestinal CD103+ dendritic cells (CD103+DC), which are known as important agents of atRA-driven immune processes, including homing of lymphocytes to the intestinal tract. Using primary human specimens and in vitro models, we show that untreated HIV-1 infection is associated with decreases in circulating atRA. This observation coincides with depletion and functional alteration of intestinal CD103+DC, along with reduced expression of gut-homing receptors on intestinal T-cells. In order to assess the therapeutic potential of atRA supplementation in HIV-1 infection, a clinical trial involving the use of isotretinoin (13-cis-retinoic acid) was conducted. Results suggest that isotretinoin may support the recovery of peripheral CD4+T-cell counts, through an as yet undetermined mechanism. Together, these data indicate that loss of atRA may abet the progression of HIV-1 disease, and that retinoic acid supplementation may have restorative benefit as an adjunct treatment to ART for HIV-1 infected individuals.